MRI Is a DNA Damage Response Adaptor during Classical Non-homologous End Joining

Hung, Putzer J; Johnson, Britney; Chen, Bo-Ruei; Byrum, Andrea K.; Bredemeyer, Andrea L.; Yewdell, William T.; Johnson, Tanya E.; Lee, Brian J.; Deivasigamani, Shruthi; Hindi, Issa; Amatya, Parmeshwar; Gross, Michael L.; Paull, Tanya T.; Pisapia, David; Chaudhuri, Jayanta; Petrini, John; Mosammaparast, Nima; Amarasinghe, Gaya K.; Zha, Shan; Tyler, Jessica K.; Sleckman, Barry P.

doi:10.1016/j.molcel.2018.06.018

Cited by 87 publications

(171 citation statements)

References 59 publications

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“…One clear example resided in a subcluster enriched in NHEJ factor-coding genes ( Figure 3C). This subcluster contained many core NHEJ factors (XRCC4, LIG4, NHEJ1), 53BP1-pathway modulators such as 53BP1, RIF1 and the shieldin components SHLD1-3 as well as the NHEJ regulator MRI/CYREN (Arnoult et al, 2017;Hung et al, 2018;Setiaputra and Durocher, 2019).…”

Section: The Bone Marrow Failure Syndrome Gene Ercc6l2 Encodes An Nhementioning

confidence: 99%

A genetic map of the response to DNA damage in human cells

Olivieri

Álvarez-Quilón

et al. 2019

Preprint

118

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The response to DNA damage is critical for cellular homeostasis, tumor suppression, immunity and gametogenesis. In order to provide an unbiased and global view of the DNA damage response in human cells, we undertook 28 CRISPR/Cas9 screens against 25 genotoxic agents in the retinal pigment epithelium-1 (RPE1) cell line. These screens identified 840 genes whose loss causes either sensitivity or resistance to DNA damaging agents. Mining this dataset, we uncovered that ERCC6L2, which is mutated in a bone-marrow failure syndrome, codes for a canonical non-homologous end-joining pathway factor; that the RNA polymerase II component ELOF1 modulates the response to transcription-blocking agents and that the cytotoxicity of the G-quadruplex ligand pyridostatin involves trapping topoisomerase II on DNA. This map of the DNA damage response provides a rich resource to study this fundamental cellular system and has implications for the development and use of genotoxic agents in cancer therapy.

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Section: The Bone Marrow Failure Syndrome Gene Ercc6l2 Encodes An Nhementioning

confidence: 99%

A genetic map of the response to DNA damage in human cells

Olivieri

Álvarez-Quilón

et al. 2019

Preprint

118

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“…12 Another recently identified protein, MRI (CYREN) forms large multimeric complexes via its interaction with key NHEJ proteins and promotes assembly and retention of DNA damage response (DDR) factors at the break points. 13 Several evidence suggest that overexpression of core NHEJ factors leads to tumor aggressiveness, radioresistance, and chemoresistance, while attenuation of the same can result in therapeutic success. [14][15][16] This makes NHEJ an ideal target for cancer therapy.…”

mentioning

confidence: 99%

Identification and characterization of novel SCR7‐based small‐molecule inhibitor of DNA end‐joining, SCR130 and its relevance in cancer therapeutics

Ray

Raul

Gopinatha

et al. 2020

Molecular Carcinogenesis

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Targeting DNA repair with small-molecule inhibitors is an attractive strategy for cancer therapy. Majority of DNA double-strand breaks in mammalian cells are repaired through nonhomologous end-joining (NHEJ). It has been shown that smallmolecule inhibitors of NHEJ can block efficient repair inside cancer cells, leading to cell death. Previously, we have reported that SCR7, an inhibitor of NHEJ can induce tumor regression in mice. Later studies have shown that different forms of SCR7 can inhibit DNA end-joining in Ligase IV-dependent manner. Recently, we have derivatized

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“…Several new cNHEJ factors ( e.g ., PAXX, and CYREN/MRI) are characterized based on their interaction with KU. Loss of PAXX or CYREN/MRI increases radiation sensitivity, but only abrogates end-ligation if XLF, a non-essential cNHEJ factor, is also lost simultaneously (7–11).…”

Section: Introductionmentioning

confidence: 99%

DNA-PKcs phosphorylation at the T2609 cluster alters the repair pathway choice during immunoglobulin class switch recombination

Crowe

Wang

Shao

et al. 2020

Preprint

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18The DNA-dependent protein kinase (DNA-PK), composed of the KU heterodimer and the 19 large catalytic subunit (DNA-PKcs), is a classical non-homologous end-joining (cNHEJ) 20 factor. Naïve B cells undergo class switch recombination (CSR) to generate antibodies with 21 different isotypes by joining two DNA double-strand breaks at different switching regions via 22 the cNHEJ pathway. DNA-PK and the cNHEJ pathway play important roles in the DNA repair 23 phase of CSR. To initiate cNHEJ, KU binds to DNA ends, and recruits and activates DNA-PK. 24 DNA-PKcs is the best-characterized substrate of DNA-PK, which phosphorylates DNA-PKcs at 25 both the S2056 and T2609 clusters. Loss of T2609 cluster phosphorylation increases radiation 26 sensitivity, suggesting a role of T2609 phosphorylation in DNA repair. Using the DNA-PKcs 5A 27 mouse model carrying an alanine substitution at the T2609 cluster, here we show that loss of 28 T2609 phosphorylation of DNA-PKcs does not affect the CSR efficiency. Yet, the CSR 29 junctions recovered from DNA-PKcs 5A/5A B cells reveal increased chromosomal translocation, 30 excess end-resection, and preferential usage of micro-homologyall signs of the alternative 31 end-joining pathway. Thus, these results uncover a role of DNA-PKcs T2609 phosphorylation 32 in promoting cNHEJ repair pathway choice during CSR. 33 34 Key points 35 Loss of T2069 cluster phosphorylation of DNA-PKcs promotes Alt-EJ-mediated CSR.36 37 58 recombination. Correspondingly, DNA-PKcs -/-(null) or Artemis -/mice are born of normal size at 59 the expected ratio but develop severe combined immunodeficiency (SCID) (4-6). Patients with 60 4hypomorphic mutations in DNA-PKcs or Artemis also develop SCID (12, 13). Mature B cells 61 undergo CSR, which replace the initially expressed IgM constant region with another 62 downstream constant region encoding a different isotype, to generate antibodies with different 63 effector functions. The cNHEJ pathway plays an important role in CSR. But in cells lacking a 64 core cNHEJ factor (e.g., Lig4 or Xrcc4), up to 25-50% of CSR can be achieved by the alternative 65 end-joining (Alt-EJ) pathway that preferentially uses microhomology (MH) at the junctions. 66 Consistent with DNA-PKcs and Artemis being dispensable for direct end-ligation, DNA-PKcs -/-67 B cells only have moderate defects in CSR (14, 15). Nevertheless, in recent high-throughput 68 sequence analyses, we found that CSR junctions recovered from DNA-PKcs -/-B cells contained 69 increased chromosomal translocations and extensive end-resection, and preferentially used MHs 70 (16), suggesting that the seemingly robust CSR achieved in DNA-PKcs -/cells is primarily 71 mediated by the Alt-EJ pathway like those in Lig4 -/or Xrcc4 -/-B cells (17, 18). Accordingly, 72 human patients with spontaneous mutations in DNA-PKcs show severe defects in both V(D)J 73 recombination and CSR and increased MH in the residual CSR junctions (12, 19). 74Active DNA-PK phosphorylates many substrates, among which, DNA-PKcs is the best-75 characterized...

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MRI Is a DNA Damage Response Adaptor during Classical Non-homologous End Joining

Cited by 87 publications

References 59 publications

A genetic map of the response to DNA damage in human cells

A genetic map of the response to DNA damage in human cells

Identification and characterization of novel SCR7‐based small‐molecule inhibitor of DNA end‐joining, SCR130 and its relevance in cancer therapeutics

DNA-PKcs phosphorylation at the T2609 cluster alters the repair pathway choice during immunoglobulin class switch recombination

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